10. Overview and classification of immunological diseases

Question 1

What can cause immunological disease?

Answer 1

Immune system may fail to control infection due to:

• Pathogen factors (evasion mechanisms)
• Host factors (immunodeficiency)

Question 2

How does immune system cause disease directly?

Answer 2

Immune system may cause disease directly

• Failure of tolerance (eg allergy/ autoimmunity)
• Immune system inappropriately activated for unknown reasons (eg inflammatory bowel disease) or for reasons that are known but poorly understood (eg asbestosis or cigarette smoke – not everybody is susceptible to lung damage)

Question 3

Mechanisms-based approach to classifying immunologically-mediated disease

Answer 3

Gell and Coombes hypersensitivity reactions types 1-4

Underlying immunological processes are all normal immune functions: the classification refers to mechanisms of disease when the immune system is inappropriately activated

The terminology is very seldom used in clinical medicine – it just helps to understand the underlying immunology

Question 4

Gell and Coombes type I hypersensitivity reactions

Answer 4

IgE antibody directed against allergen, triggers mast cell degranulation

e.g. seasonal rhinitis, cat allergy

Question 5

Gell and Coombes type II hypersensitivity

Answer 5

A pathogenic antibody directly causing disease

e.g. autoimmune haemolysisi

Question 6

Type III hypersensitivity reactions

Answer 6

antibody-antigen complex-mediated disease

e.g. serum sickness, systemic lupus erythmatosis

Question 7

Type IV hypersensitivity reaction

Answer 7

Inflammation directly mediated by T cells

e.g. contact dermatitis, tuberculin reaction

Question 8

Type 1 hypersensitivity: IgE-mediated allergy

Answer 8

B cells class switch to IgE antibody, and secreted IgE is picked up by tissue mast cells and circulating basophils

allergen-specific IgE antibodies crosslink by allergen, activating the mast cell

Mast cell rapidly ‘degranulates’ releasing histamine, tryptase and other pre-formed mediators

Pharmacological effects of histamine lead to symptoms in the affected organ(s)

In health, mediates parasite immunity

Question 9

Type 2 hypersensitivity:AB blood system and transfusion medicine

Answer 9

Pathology directly mediated by antibodies

E.g. Mismatch blood transfusion reactions

IgM antibodies against AB antigens develop during first year of life

The antibodies are an example of isoantibodies – develop against similar antigens on surface of gut bacteria and cross-react with red cell antigens

Group AB: both antigens, no antibodies

Group O: both antibodies, no antigen

Question 10

Type 2 hypersensitivity: haemolytic disease of the newborn

Answer 10

‘D’ antigen (Rhesus) is a secondary blood classification after ABO

Majority of the population are D+

Mother may be sensitised by exposure to fetal red cells during pregnancy e.g. in parturition or trauma

Antibodies may cause disease in subsequent pregnancies

Question 11

Haemolytic disease of the newborn in the clinic

Answer 11

Autoimmune haemolysis highly deleterious to fetus:
- Growth retardation, cardiovascular failure, ‘hydrops fetalis’, neurotoxicity from high bilirubin levels

Rhesus-negative mothers with rhesus+ partner are given anti-D IgG during pregnancy

• At 28 weeks routinely
• After accidents, miscarriage or surgical delivery

Binds to fetal red cells entering circulation; fetal red cells then destroyed, preventing sensitisation

Risk of maternal sensitisation reduced from 16% per pregnancy to 0.1%

Question 12

Autoimmune haemolysis

Answer 12

Type 2 hypersensitivity

RBCs plus anti-RBC autoantibodies

Leads to:

• FCR+ cells in fixed mononuclear phagocytic system -> phagocytosis and RBC destruction
• Complement activation and intravascular haemolysis -> lysis and RBC destruction

Question 13

Type III hypersensitivity

Answer 13

Disease caused by complexes of antibody and antigen

These complexes are normal
- Usually soluble, removed in spleen

In some situations they become insoluble and cause disease e.g. in:

• Large quantity of antigen
• Large quantity of antibody
• Interaction between the two is very strong
• Complexes are of the correct size

Question 14

Local immune complex disease

Answer 14

Painful lesions in the fingertip pulp due to deposition of circulating immune complexes

May be seen in infective endocarditis (Osler’s nodes)

May be seen in other diseases with immune complex deposition (eg SLE)

Question 15

Type III hypersensitivity: serum sickness

Answer 15

A ‘generalised’ transient immune complex-mediated syndrome

Mainly results from injection of certain immunogenic drugs or anti-sera produced in animals eg after snake evenomation

• Rash
• Fever
• Arthritis
• Glomerulonephritis

Question 16

Type III hypersensitivity: hypersensitivity pneumonitis

Answer 16

Also known as extrinsic allergic alveolitis (EAA)

Patient becomes sensitised to an environmental antigen by repeated exposure, producing large quantities of IgG antibodies

Immune complexes form in the lung upon re-exposure causing shortness of breath and cough

Mould spores in hay (farmers lung)
Pigeon feathers and stool (pigeon-fanciers lung)
Initially transient, lung scarring with repeated exposure

Question 17

Type IV hypersensitivity: Delayed-type hypersensitivity

Answer 17

Reactions are mediated by antigen-specific effector T cells

Because it takes time to process and present antigen, these reactions do not develop for at least 24 hours following exposure

In the skin, known as contact dermatitis

Question 18

Contact dermatitis: sensitisation

Answer 18

Sensitising agents are typically highly reactive small molecules which can penetrate skin

These react with self proteins to create protein-hapten* complexes that are picked up by Langerhans cells, which migrate to regional lymph nodes
Examples are nickel and molecules in perfume/ cosmetics

Question 19

What do Langerans cells do in contact dermatitis?

Answer 19

The Langerhans cells process and present the antigen together with MHCII

In some susceptible individuals, the complexes are recognised as foreign

The activated T cells then migrate to the dermis

Question 20

What is a hapten?

Answer 20

Hapten=small molecule which cannot produce an immune response by itself, but can bind to a protein to alter its immunogenicity

Question 21

Tuberculin skin test (TST): another example of a type IV hypersensitivity reaction

Answer 21

Used to determine previous EXPOSURE to TB
Tuberculin injected intradermally (tuberculin=complex mixture of antigens derived from MTB)
Local inflammatory response evolves over 24-72 hours if previously exposed
Mediated by Th1 cells

Question 22

Can you detect TB by blood test?

Answer 22

Detection of TB-specific Th1 cells in vitro by interferon gamma release assay (IGRA)

Question 23

Result of IGRA

Answer 23

if previous TB exposure:
Memory Th1 cells recognise antigen. Because this is a secondary immune response, they are ‘primed’ and release cytokines within this short timeframe

no previous TB exposure:
No primed memory T cells specific for MTB. No interferon gamma produced in such a short timeframe

Question 24

Pros of Gell and Coombes classification

Answer 24

The only successful attempt to classify disease by mechanism

A useful framework to describe & understand various diseases

Question 25

Cons of Gell and coombes

Answer 25

Cons
Not particularly useful in clinical practice
Oversimplifies the immunology
Even in apparently simple situations such as autoimmune haemolysis (type II hypersensitivity), many components of the immune system are involved

Many diseases are much more complex, particularly chronic inflammatory diseases.
Involve multiple immunological effector mechanisms and aren’t well-described in this framework eg
- Rheumatoid arthritis
- Chronic asthma
- Inflammatory bowel disease etc etc